tbuckley/cabot-search huggingface dataset:
Novel causative variants of VEXAS in UBA1 detected through whole genome transcriptome sequencing in a large cohort of hematological malignancies
Authors: Maki Sakuma, Piers Blombery, Manja Meggendorfer, Claudia Haferlach, Markus Lindauer, Uwe M. Martens, Wolfgang Kern, Torsten Haferlach, Wencke Walter
Journal: Leukemia (2023)

UBA1 is an X-linked gene and encodes an ubiquitin-activating enzyme. Three somatic mutations altering the alternative start codon (M41) in UBA1 in hematopoietic precursor cells have recently been described, resulting in a syndrome of severe inflammation, cytopenias, and the presence of intracellular vacuoles in hematopoietic precursors - termed VEXAS syndrome, a predominantly male disease. Here we present a patient with clinical features of VEXAS who harbored two novel somatic variants in UBA1 (I894S and N606I). To better understand the clinical relevance and biological consequences of non-M41 (UBA1non-M41) variants, we analyzed the whole genome and transcriptome data of 4168 patients with hematological malignancies and detected an additional 16 UBA1non-M41 putative somatic variants with a clear sex-bias in patients with myeloid malignancies. Patients diagnosed with myeloid malignancies carrying UBA1non-M41 putative somatic variants either had vacuoles or immunodysregulatory symptoms. Analysis of the transcriptome confirmed neutrophil activation in VEXAS patients compared to healthy controls but did not result in a specific transcriptomic signature of UBA1M41 patients in comparison with MDS patients. In summary, we have described multiple putative novel UBA1non-M41 variants in patients with various hematological malignancies expanding the genomic spectrum of VEXAS syndrome.
Treg-selective IL-2 starvation synergizes with CD40 activation to sustain durable responses in lymphoma models
Authors: Kristin Stirm, Peter Leary, Daria Wüst, Dominique Stark, Nicole Joller, Ufuk Karakus, Onur Boyman, Alexandar Tzankov, Anne Müller
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Roughly half of all diffuse large B-cell lymphomas (DLBCLs) are infiltrated by large numbers of regulatory T-cells (Tregs). Although the presence of ‘effector’ Tregs in particular is associated with an inferior prognosis in patients on standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) immunochemotherapy, the role of this cell type during lymphoma initiation and progression is poorly understood. Methods Here, we use tissue microarrays containing prospectively collected DLBCL patient specimens, as well as data from publicly available cohorts to explore the mutational landscape of Treg-infiltrated DLBCL. We further take advantage of a model of MYC-driven lymphoma to mechanistically dissect the contribution of Tregs to lymphoma pathogenesis and to develop a strategy of Treg-selective interleukin-2 (IL-2) starvation to improve immune control of MYC-driven lymphoma. Results We find that all genetic DLBCL subtypes, except for one characterized by co-occurring MYD88 / CD79 mutations, are heavily infiltrated by Tregs. Spectral flow cytometry and scRNA-sequencing reveal the robust expression of functional and immunosuppressive markers on Tregs infiltrating MYC-driven lymphomas; notably, we find that intratumoral Tregs arise due to local conversion from naïve CD4 + precursors on tumor contact. Treg ablation in Foxp3 iDTR mice, or by antibody-mediated Treg-selective blockade of IL-2 signaling, strongly reduces the lymphoma burden. We identify lymphoma B-cells as a major source of IL-2, and show that the effects of Treg depletion are reversed by the simultaneous depletion of Foxp3-negative CD4 + T-cells, but not CD8 + T-cells or natural killer (NK) cells. The inhibition of ATP hydrolyzation and adenosine production by Tregs at least partly phenocopies the effects of Treg depletion. Treg depletion further synergizes with pro-apoptotic CD40 activation to sustain durable responses. Conclusion The combined data implicate Tregs as a potential therapeutic target in DLBCL, especially in combination with other immunotherapies.
KIR/KIR-ligand genotypes and clinical outcomes following chemoimmunotherapy in patients with relapsed or refractory neuroblastoma: a report from the Children’s Oncology Group
Authors: Amy K Erbe, Mitch B Diccianni, Rajen Mody, Arlene Naranjo, Fan F Zhang, Jen Birstler, KyungMann Kim, Arika S Feils, Jung-Tung Hung, Wendy B London, Barry L Shulkin, Varsha Mathew, Marguerite T Parisi, Sabah Servaes, Shahab Asgharzadeh, John M Maris, Julie Park, Alice L Yu, Paul M Sondel, Rochelle Bagatell
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background In the Children’s Oncology Group ANBL1221 phase 2 trial for patients with first relapse/first declaration of refractory high-risk neuroblastoma, irinotecan and temozolomide (I/T) combined with either temsirolimus (TEMS) or immunotherapy (the anti-GD2 antibody dinutuximab (DIN) and granulocyte macrophage colony stimulating factory (GM-CSF)) was administered. The response rate among patients treated with I/T/DIN/GM-CSF in the initial cohort (n=17) was 53%; additional patients were enrolled to permit further evaluation of this chemoimmunotherapy regimen. Potential associations between immune-related biomarkers and clinical outcomes including response and survival were evaluated. Methods Patients were evaluated for specific immunogenotypes that influence natural killer (NK) cell activity, including killer immunoglobulin-like receptors (KIRs) and their ligands, Fc gamma receptors, and NCR3. Total white cells and leucocyte subsets were assessed via complete blood counts, and flow cytometry of peripheral blood mononuclear cells was performed to assess the potential association between immune cell subpopulations and surface marker expression and clinical outcomes. Appropriate statistical tests of association were performed. The Bonferroni correction for multiple comparisons was performed where indicated. Results Of the immunogenotypes assessed, the presence or absence of certain KIR and their ligands was associated with clinical outcomes in patients treated with chemoimmunotherapy rather than I/T/TEMS. While median values of CD161, CD56, and KIR differed in responders and non-responders, statistical significance was not maintained in logistic regression models. White cell and neutrophil counts were associated with differences in survival outcomes, however, increases in risk of event in patients assigned to chemoimmunotherapy were not clinically significant. Conclusions These findings are consistent with those of prior studies showing that KIR/KIR-ligand genotypes are associated with clinical outcomes following anti-GD2 immunotherapy in children with neuroblastoma. The current study confirms the importance of KIR/KIR-ligand genotype in the context of I/T/DIN/GM-CSF chemoimmunotherapy administered to patients with relapsed or refractory disease in a clinical trial. These results are important because this regimen is now widely used for treatment of patients at time of first relapse/first declaration of refractory disease. Efforts to assess the role of NK cells and genes that influence their function in response to immunotherapy are ongoing. Trial registration number NCT01767194 .
Targeting tumor-associated macrophages for successful immunotherapy of ovarian carcinoma
Authors: Iva Truxova, David Cibula, Radek Spisek, Jitka Fucikova
Journal: Journal for ImmunoTherapy of Cancer (2023)

Epithelial ovarian cancer (EOC) is among the top five causes of cancer-related death in women, largely reflecting early, prediagnosis dissemination of malignant cells to the peritoneum. Despite improvements in medical therapies, particularly with the implementation of novel drugs targeting homologous recombination deficiency, the survival rates of patients with EOC remain low. Unlike other neoplasms, EOC remains relatively insensitive to immune checkpoint inhibitors, which is correlated with a tumor microenvironment (TME) characterized by poor infiltration by immune cells and active immunosuppression dominated by immune components with tumor-promoting properties, especially tumor-associated macrophages (TAMs). In recent years, TAMs have attracted interest as potential therapeutic targets by seeking to reverse the immunosuppression in the TME and enhance the clinical efficacy of immunotherapy. Here, we review the key biological features of TAMs that affect tumor progression and their relevance as potential targets for treating EOC. We especially focus on the therapies that might modulate the recruitment, polarization, survival, and functional properties of TAMs in the TME of EOC that can be harnessed to develop superior combinatorial regimens with immunotherapy for the clinical care of patients with EOC.
Predictive biomarkers for PD-1/PD-L1 checkpoint inhibitor response in NSCLC: an analysis of clinical trial and real-world data
Authors: WeiQing Venus So, David Dejardin, Eva Rossmann, Jehad Charo
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Many biomarkers have been proposed to be predictive of response to anti-programmed cell death protein-1 (PD-1)/anti-programmed death ligand-1 (PD-L1) checkpoint inhibitors (CPI). However, conflicting observations and lack of consensus call for an assessment of their clinical utility in a large data set. Using a combined data set of clinical trials and real-world data, we assessed the predictive and prognostic utility of biomarkers for clinical outcome of CPI in non-small cell lung cancer (NSCLC). Methods Retrospective cohort study using 24,152 patients selected from 71,850 patients with advanced NSCLC from electronic health records and 9 Roche atezolizumab trials. Patients were stratified into high and low biomarker groups. Correlation with treatment outcome in the different biomarker groups was investigated and compared between patients treated with CPI versus chemotherapy. Durable response was defined as having complete response/partial response without progression during the study period of 270 days. Results Standard blood analytes (eg, albumin and lymphocyte) were just prognostic, having correlation with clinical outcome irrespective of treatment type. High expression of PD-L1 on tumors (≥50% tumor cell staining) were specifically associated with response to CPI (OR 0.20; 95% CI 0.13 to 0.30; p&lt;0.001). The association was stronger in patients with non-squamous than squamous histology, with smoking history than non-smokers, and with prior chemotherapy than first-line CPI. Higher tumor mutational burden (TMB) (≥10.44 mut/Mb) was also specifically associated with durable response to CPI (OR=0.40; 95% CI 0.29 to 0.54; p&lt;0.001). The combination of high TMB and PD-L1 expression was the strongest predictor of durable response to CPI (OR=0.04; 95% CI 0.00 to 0.18; p&lt;0.001). There was no significant association between PD-L1 or TMB levels with response to chemotherapy, suggesting a CPI-specific predictive effect. Conclusions Standard blood analytes had just prognostic utility, whereas tumor PD-L1 and TMB specifically predicted response to CPI in NSCLC. The combined high TMB and PD-L1 expression was the strongest predictor of durable response. PD-L1 was also a stronger predictor in patients with non-squamous histology, smoking history or prior chemotherapy.
Generation of TGFβR2(-1) neoantigen-specific HLA-DR4-restricted T cell receptors for cancer therapy
Authors: Natalia Plewa, Lucia Poncette, Thomas Blankenstein
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Adoptive transfer of patient’s T cells, engineered to express a T cell receptor (TCR) with defined novel antigen specificity, is a convenient form of cancer therapy. In most cases, major histocompatibility complex (MHC) I-restricted TCRs are expressed in CD8 + T cells and the development of CD4 + T cells engineered to express an MHC II-restricted TCR lacks behind. Critical is the choice of the target antigen, whether the epitope is efficiently processed and binds with high affinity to MHC molecules. A mutation in the transforming growth factor β receptor 2 (TGFβR2(-1)) gene creates a frameshift peptide caused by the deletion of one adenine (-1) within a microsatellite sequence. This somatic mutation is recurrent in microsatellite instable colorectal and gastric cancers and, therefore, is a truly tumor-specific antigen detected in many patients. Methods ABabDR4 mice, which express a diverse human TCR repertoire restricted to human MHC II molecule HLA-DRA/DRB1*0401 (HLA-DR4), were immunized with the TGFβR2(-1) peptide and TGFβR2(-1)-specific TCRs were isolated from responding CD4 + T cells. The TGFβR2(-1)-specific TCRs were expressed in human CD4 + T cells and their potency and safety profile were assessed by co-cultures and other functional assays. Results We demonstrated that TGFβR2(-1) neoantigen is immunogenic and elicited CD4 + T cell responses in ABabDR4 mice. When expressed in human CD4 + T cells, the HLA-DR4 restricted TGFβR2(-1)-specific TCRs induced IFNy expression at low TGFβR2(-1) peptide amounts. The TGFβR2(-1)-specific TCRs recognized HLA-DR4 + lymphoblastoid cells, which endogenously processed and presented the neoantigen, and colorectal cancer cell lines SW48 and HCT116 naturally expressing the TGFβR2(-1) mutation. No MHC II alloreactivity or cross-reactivity to peptides with a similar TCR-recognition motif were observed, indicating the safety of the TCRs. Conclusions The data suggest that HLA-DR4-restricted TCRs specific for the TGFβR2(-1) recurrent neoantigen can be valuable candidates for adoptive T cell therapy of a sizeable number of patients with cancer.
Concurrent durvalumab and radiation therapy (DUART) followed by adjuvant durvalumab in patients with localized urothelial cancer of bladder: results from phase II study, BTCRC-GU15-023
Authors: Monika Joshi, Leonard Tuanquin, Junjia Zhu, Vonn Walter, Todd Schell, Matthew Kaag, Deepak Kilari, Jiangang Liao, Sheldon L Holder, Hamid Emamekhoo, Alexander Sankin, Suzzane Merrill, Hong Zheng, Joshua Warrick, Ralph Hauke, Benjamin Gartrel, Mark Stein, Joseph Drabick, David J Degraff, Yousef Zakharia
Journal: Journal for ImmunoTherapy of Cancer (2023)

Patients with bladder cancer (BC) who are cisplatin ineligible or have unresectable disease have limited treatment options. Previously, we showed targeting programmed death-ligand 1 (PD-L1) with durvalumab (durva) and radiation therapy (RT) combination was safe in BC. We now report results from a phase II study evaluating the toxicity and efficacy of durva and RT in localized BC.This is a single-arm, multi-institutional phase II study; N=26. Enrolled patients had pure or mixed urothelial BC (T2-4 N0-2 M0) with unresectable tumors and were unfit for surgery or cisplatin ineligible. Patients received durva concurrently with RT ×7 weeks, followed by adjuvant durva × 1 year.(A) progression-free survival (PFS) at 1 year and (B) disease control rate (DCR) post adjuvant durva. Key secondary endpoints: (A) complete response (CR) post durvaRT (8 weeks), (B) overall survival (OS), (C) PFS and (D) toxicity. Correlative studies included evaluation of baseline tumor and blood (baseline, post durvaRT) for biomarkers.Median follow-up was 27 months. Evaluable patients: 24/26 post durvaRT, 22/26 for DCR post adjuvant durva, all patients for PFS and OS. Post adjuvant durva, DCR was seen in 72.7%, CR of 54.5%. 1-year PFS was 71.5%, median PFS was 21.8 months. 1-year OS was 83.8%, median OS was 30.8 months. CR at 8 weeks post durvaRT was 62.5%. Node positive (N+) patients had similar median PFS and OS. DurvaRT was well tolerated. Grade ≥3 treatment-related adverse events: anemia, high lipase/amylase, immune-nephritis, transaminitis, dyspnea (grade 4-COPD/immune), fatigue, rash, diarrhea and scleritis. No difference in outcome was observed with PD-L1 status of baseline tumor. Patients with CR/PR or SD had an increase in naïve CD4 T cells, a decrease in PD-1+CD4 T cells at baseline and an increase in cytokine-producing CD8 T cells, including interferon gamma (IFNγ) producing cells, in the peripheral blood.Durva with RT followed by adjuvant durva was safe with promising efficacy in localized BC patients with comorbidities, including N+ patients. Larger randomized studies, like S1806 and EA8185, are needed to evaluate the efficacy of combining immunotherapy and RT in BC.NCT02891161.
ANKRD22 is a potential novel target for reversing the immunosuppressive effects of PMN-MDSCs in ovarian cancer
Authors: Huanhuan Chen, Keqing Yang, Lingxiao Pang, Jing Fei, Yongliang Zhu, Jianwei Zhou
Journal: Journal for ImmunoTherapy of Cancer (2023)

Ovarian cancer is the deadliest type of malignant gynecological tumor. Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are involved ovarian cancer and are closely related to adverse outcomes. However, the immunosuppressive mechanism of PMN-MDSCs remains elusive.The types and numbers of ANKRD22-expressing cells were investigated by bioinformatics analysis and immunohistochemical staining. Ankrd22-/- C57BL/6 mice were constructed with CRISPR-Cas9 technology. Mouse PMN-MDSCs were obtained from bone marrow (BM)-derived CD11b+Ly6G+Ly6Clow cells sorted by fluorescence-activated cell sorting with treatment of GM-CSF and IL-6, and the immunosuppressive activity of PMN-MDSCs was evaluated by flow cytometry (FCM) and ELISA. The expression level of CCR2 and the exogenous glucose uptake capacity were determined by FCM. RT-qPCR was used to detect ANKRD22 expression in CD11b+HLA-DR-CD14-CD15+ cells from human ovarian cancer tissues, and the correlations of ANKRD22 expression with the clinical characteristics and prognosis of patients were evaluated by the χ2 test.We identified a novel protein involved in regulating the immunosuppressive ability of PMN-MDSCs, ANKRD22. Ankrd22 expression was high in mouse CD11b+Ly6G+Ly6Clow cells and could be significantly downregulated after exposure to a simulated microenvironmental stimulus. Knockout of Ankrd22 increased the expression level of CCR2 of CD11b+Ly6G+Ly6Clow cells and the immunosuppressive activity of PMN-MDSCs. BM-derived CD11b+Ly6G+Ly6Clow cells of Ankrd22-/- mice significantly promoted the proliferation of ovarian cancer cells in tumor xenograft mouse models. Mechanistically, RNA sequencing showed that Wdfy1 expression was obviously increased in Ankrd22-knockout BM-derived CD11b+Ly6G+ Ly6Clow cells and that ectopic expression of Wdfy1 increased the levels of Arg1, Inos, Ido and Pdl1 in Ankrd22+/+ PMN-MDSCs derived from BM-derived CD11b+Ly6G+Ly6Clow cells. Surprisingly, an ANKRD22-activating candidate small-molecule compound attenuated the immunosuppressive activity of Ankrd22+/+ PMN-MDSCs. Finally, we found that low ANKRD22 levels in CD11b+HLA-DR-CD14-CD15+ cells derived from primary ovarian tissues were associated with a more advanced International Federation of Gynecology and Obstetrics stage, a higher recurrence rate, and a higher neutrophil-to-lymphocyte ratio.These results suggest that ANKRD22 is a potential novel target for reversing the immunosuppressive effects of PMN-MDSCs.
Associations of improved air quality with lung function growth from childhood to adulthood: the BAMSE study
Authors: Zhebin Yu, Simon Kebede Merid, Tom Bellander, Anna Bergström, Kristina Eneroth, Antonios Georgelis, Jenny Hallberg, Inger Kull, Petter Ljungman, Susanna Klevebro, Massimo Stafoggia, Gang Wang, Göran Pershagen, Olena Gruzieva, Erik Melén
Journal: European Respiratory Journal (2023)

The beneficial effect of improving air quality on lung function development remains understudied. We assessed associations of changes in ambient air pollution levels with lung function growth from childhood until young adulthood in a Swedish cohort study.In the prospective birth cohort BAMSE (Children, Allergy, Environment, Stockholm, Epidemiology (in Swedish)), spirometry was conducted at the 8-year (2002-2004), 16-year (2011-2013) and 24-year (2016-2019) follow-ups. Participants with spirometry data at 8 years and at least one other measurement in subsequent follow-ups were included (1509 participants with 3837 spirometry measurements). Ambient air pollution levels (particulate matter with diameter ≤2.5 μm (PM2.5), particulate matter with diameter ≤10 μm (PM10), black carbon (BC) and nitrogen oxides (NO x )) at residential addresses were estimated using dispersion modelling. Linear mixed effect models were used to estimate associations between air pollution exposure change and lung function development.Overall, air pollution levels decreased progressively during the study period. For example, the median (interquartile range (IQR)) level of PM2.5 decreased from 8.24 (0.92) μg·m-3 during 2002-2004 to 5.21 (0.67) μg·m-3 during 2016-2019. At the individual level, for each IQR reduction of PM2.5 the lung function growth rate increased by 4.63 (95% CI 1.64-7.61) mL per year (p<0.001) for forced expiratory volume in 1 s and 9.38 (95% CI 4.76-14.00) mL per year (p<0.001) for forced vital capacity. Similar associations were also observed for reductions of BC and NO x . Associations persisted after adjustment for potential confounders and were not modified by asthma, allergic sensitisation, overweight, early-life air pollution exposure or dietary antioxidant intake.Long-term reduction of air pollution is associated with positive lung function development from childhood to young adulthood.
Nasal nitric oxide measurement in children for the diagnosis of primary ciliary dyskinesia: European Respiratory Society technical standard
Authors: Nicole Beydon, Panayiotis Kouis, June K. Marthin, Philipp Latzin, Murielle Colas, Stephanie D. Davis, Eric Haarman, Amanda Lea Harris, Claire Hogg, Emma Kilbride, Claudia E. Kuehni, Diana Marangu, Kim G. Nielsen, Catherine Pendergrast, Phil Robinson, Nisreen Rumman, Matthew Rutter, Woolf T. Walker, Thomas Ferkol, Jane S. Lucas
Journal: European Respiratory Journal (2023)

Nasal nitric oxide (nNO) is extremely low in most people with primary ciliary dyskinesia (PCD) and its measurement is an important contributor to making the diagnosis. Existing guidelines and technical standards focus on nNO measurements in older, cooperative children using chemiluminescence analysers. However, measurements of nNO in pre-school-age children (age 2–5 years) may facilitate early diagnosis and electrochemical rather than chemiluminescence analysers are widely used. Pre-schoolers often need different methods to be employed when measuring nNO. Hence, a European Respiratory Society Task Force has developed this technical standard as the first step towards standardising sampling, analysis and reporting of nNO measured as part of the diagnostic testing for PCD in all age groups, including pre-school-age children. Furthermore, we considered both chemiluminescence and electrochemical analysers that are in use worldwide. There was a paucity of quality evidence for electrochemical analysers and sampling methods used in young children, and the Task Force proposes future research priorities to allow updates of this technical standard.